Potential biomarkers for chronic kidney disease. Diana Lebherz-Eichinger 3rd of october

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1 Potential biomarkers for chronic kidney disease Diana Lebherz-Eichinger 3rd of october

2 Background Course of Chronic kidney disease Increased cell death and counterregulation

3 Cytokeratin-18 as biomarker for CKD? HSPs as biomarker for CKD?

4 Cytokeratin-18 as biomarker for CKD?

5 Background CK18 Cytokeratin 18 Intermediate filament protein ubiquitous expressed by epithelial and parenchymal cells

6 Background CK18 Total CK-18 Necrosis total CK-18 Serum levels

7 Background CK18 Total CK-18 Apoptosis total CK-18 cleaved by caspases 3, 7 and 9 Caspase 7 Necrosis total CK-18 Serum levels Caspase cleaved CK-18

8 Background CK18 CK -18 as biomarker for CKD? comparison CK - 18 Albumin

9 Background CK18 CK -18 as biomarker for CKD? comparison CK - 18 Albumin 48 kda 430 AA cck 18, 30 AA Marker for cell death 66 kda 585 AA Mikroalbuminurie: 7 % Elevated in urine of patients with CKD?

10 Serum Results CK18 total CK -18 levels in 120 patients + 20 controls

11 Serum Results CK18 total CK -18 levels in 120 patients + 20 controls Urine

12 Serum Results CK18 total CK -18 levels in 120 patients + 20 controls Urine

13 Results CK18 ROC curve analysis total CK-18 levles AUC ( ) p<0.001 AUC ( ) p<0.001 AUC ( ) p<0.001 AUC ( ) p=0.015

14 Results CK18 Findings in patients with CKD - summary

15 Results CK18 Findings in patients with CKD - summary caspase cleaved CK-18 NOT elevated in serum or urine

16 Results CK18 Findings in patients with CKD - summary caspase cleaved CK-18 NOT elevated in serum or urine total CK-18 significant elevated in serum and urine

17 Results CK18 Findings in patients with CKD - summary caspase cleaved CK-18 NOT elevated in serum or urine total CK-18 significant elevated in serum and urine indication for increased necrotic cell death

18 Heat shock proteins as biomarkers for CKD? Wisniewska M, Lehtio L, Arrowsmith C.H., et al. Hsp70 protein

19 Background HSP Heat shock proteins Cellular defense mechanisms Inhibit apoptotic pathways

20 Background HSP Heat shock proteins Cellular defense mechanisms Inhibit apoptotic pathways HSP27: 27kDa - Inhibits caspase activation - Anti-oxidant qualities

21 Background HSP Heat shock proteins Cellular defense mechanisms Inhibit apoptotic pathways HSP27: 27kDa - Inhibits caspase activation - Anti-oxidant qualities HSP70: 70kDa - Inhibits intrinsic and extrinsic pathways - Inhibits cell damage by urea in vitro

22 Background HSP Heat shock proteins Cellular defense mechanisms Inhibit apoptotic pathways HSP27: 27kDa - Inhibits caspase activation - Anti-oxidant qualities HSP70: 70kDa - Inhibits intrinsic and extrinsic pathways - Inhibits cell damage by urea in vitro - Unchanged serum levels in children with CKD (Musial et al. 2010) - Decreased expression in blood monocytes of adults with CKD (Marzec et al. 2009)

23 Results HSP HSP70 levels HSP-70, pg/ml Urine (119 patients, 23 controls) ns ns p = p = ns 0 Healthy CKD 1 CKD 2 CKD 3 CKD 4 CKD 5 Serum levels: technical limitations, data for remaining 42 patients not significant Fractional excretion: significant elevated in stage 5 (p = )

24 Serum HSP-27, pg/ml Results HSP HSP27 levels in 119 patients + 23 controls p < p < p < ns ns Healthy CKD 1 CKD 2 CKD 3 CKD 4 CKD 5

25 Serum HSP-27, pg/ml Urine HSP-27, pg/ml Results HSP HSP27 levels in 119 patients + 23 controls p < p < p < p < ns p < ns 6000 ns ns 6000 ns Healthy CKD 1 CKD 2 CKD 3 CKD 4 CKD 5 0 Healthy CKD 1 CKD 2 CKD 3 CKD 4 CKD 5

26 Fractional HSP-27 excretion, % Serum HSP-27, pg/ml Urine HSP-27, pg/ml Results HSP HSP27 levels in 119 patients + 23 controls p < p < p < p < ns p < ns 6000 ns ns 6000 ns Healthy CKD 1 CKD 2 CKD 3 CKD 4 CKD 5 0 Healthy CKD 1 CKD 2 CKD 3 CKD 4 CKD 5 20 p < p < p = p < p = Healthy CKD 1 CKD 2 CKD 3 CKD 4 CKD 5

27 Results HSP ROC curve analysis A HSP27 B 1.0 Serum HSP27 - Stage 3 or greater 1.0 Fractional HSP27 excretion - Stage 1 or higher Sensitivity AUC ( ) p < Sensitivity AUC ( ) p < Specificity 1 - Specificity

28 Results Summary total CK-18 significant elevated in serum and urine indication for increased necrotic cell death Heat shock proteins significant elevated in serum and urine counterregulation to increased systemic stress levels

29 Thank you for your attenttion Potential biomarkers for chronic kidney disease

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31 Correlation CK-18

32 Correlation of HSP serum and urine levels with clinical and kidney function parameters. HSP27 serum HSP27 urine HSP70 urine Age (119 pairs) r = , p < r = , p = r = , p = Estimated glomerular filtration rate (119 pairs) r = , p < r = , p = r = , p = Total urine protein (118 pairs) r = , p < r = , p = r = , p = Urine albumin (92 pairs) r = , p = r = , p = r = , p = Creatinine clearance (33 pairs) r = , p = r = , p = r = , p = CRP (118 pairs) r = , p = r = , p = r = , p =